Derivatives of 1-hydroxyphenyl-3-aminobutane and processes for their production



Patented Sept. 3, 1946 f- DERIVATIVES 50F 1-HYDRUXYPHENYD-3- AMINOBUTANE ANn mtocnssnszvnon ....rrnnm .PBQDUCTION Fiitz" Kiilz, Frankfort- @vested in. the Alien Property'flustodian *No Dra'iving; Appli'cation flctoberrmg11941, Serial many February 2I 1940 i. 1 i .The invention concerns. new derivatives of. 1- :1.hydroxyphenyl-3earninobutane and processes for their production.

iIt'i isi known that: B: (pehydro'xyphenyl r-isos xpropylamine "and its derivati'ves are characterized by a special efiect on circulation.

Mannich has prepared the next higher homologue amine, the 1 hydroxyphnyl-3-aminobutane, from p-hydroxybenz ylacetone, by preparing and'rdU'cing the 'ditim. 5 "(Archiv fiir Pharmazie, Vol; 265;""( 1'92'7)', 23), i It has beenstated that this comp'ound m- -comparison 'with the -above nam'ed'ompound has a lessdistinct eifect-on circulation, while analgesic properties may be just detectable, bu-tare far too-:weakttobe-suitedfor practical purposes. It has been found that'alike the known norbasedei-ivatives" f 1-0; "-por -m'-'hyd-roxv- --"phenyl'-3-*amiriobutaneof "the" general formula H 0 0 511413112 0 Hz C H;C H3

T-x-rt-H in which X re resents alkyl, alkenyl=,'"cyclo iiLlkyl, cyclo alkenyl, ar'alkyl or aralkenyl "have no ability ofv effectingcirculation; but unlike-the known nor-base have excellent analgesic properties. Among the alkyl derivatives; for example among *the methyl-,- *ethyl- "propyl-j butyl-i "isobutyl -am'yl-; is'oamylderivatives "the met-hyl "deriva- "nary efficacious"analgesicproperties. The other alkyl derivatives have less outspoken analgesic properties. .Qompounds with an-alkyl. with more than 6 carbon atoms areless important for practical purposes. This rule is valid, independently" of the-"position ofthe OH group'f that is' whether it'is in' the'o-y p-"or m-position. Also alkenyb, "for- 'example"allyl-,' cyclo alkyl-f fonexam'rlle cyclo"pentyl=" or cycle 'heky1;"cyc1o 'ialkenylffor example cyclo pentenyl or"'cyclo" hexe'nylfaralkyl-t' forfrexafnple' benzy1-, pheriyl. ethyl-,- -or aralkenyl-, for"'-example "phenyl allyl-derivatives, have good analgesicsproperties.

The neW-canalgesics: mayi be-prepareddaccordwing? :to -various-rmethods. 1 1..-hydroxyphenyl-'3- :aminobutane :may iberitreatedr irri "kIlfOWII manner L'Withk "agentsjwhichl are suited for .aintroductionfof i'the desi-r'ed hydrocarbonzresidue for example with h'alogenides -fiof I'thei corresponding hydrocarbons g I:lor iWitltfcorresponding aldehydes orf-ketoneai in which latter: casethe 'forining" Schiffs base must be hydrogenatedfior according to Leuckart 'wallach. -One -may; :1 iowever; -proceedi vice- .versaii zthat is from 1-hydroxypheny1-3-ha1ogenbutane, and react this with a primary amine.

' The new "compounds may also-beobtained by starting from hydroxybenzyl acetone, condensing 5 same with a primary amine or -ammonia and hyv-drogenatingnthe forming condensation products. "lf ammonia is used, the-obtained -l-hydrogry- -phenyl-B amin butane -must be treated with agents; which are suitabl -ror introductiomoi 10 thehydrocarbonxresidue.

Themostsimple methodlof producing. the .compound e according -tomthe invention consists in condensing 1 hydroxybenzalacetone withprimary t amineso-r-ammonia. JAlso in this case condensation lfi productsare obtained; thecarbon carbon. double .bond and --the carbon nitrogen double bond of P which-maybe hydrogenated in asingl working t process, toreexample -catalytica1ly-by hydrogen r. in the presence of platinumr If ammonia :is em- -p10yed. ufor the: production of the condensation products-the forming 1ehydroxyphenyl-a-amino- --=butane must.betreatedagain with agents, which i are suitable for introduction of the desired hy- 'drocarbon residue.

' .Thecompounds according to thednvention Jmay also be prepared from l-phenyl-S-aminobu- --tanes substituted accordingly at theHnitrogen by l. or. .aralkenyl .by. n-itration in the benzene ring, re-

QA .duction offlthe' obtained. nitr compound to.v the amino compound, diaz'otizing of the amino group at 'the' benzene ring with nitrous acid and converting intothe desired'hydroxy compounds by boiling,

=Fina-llythe analgesics according: tothe invenncstion may be prepared fromthe corresponding -alkoxy --compounds by splitting or? the etherified .Joxygroup for exampleby treatment withhydroshalogenic acid, 4 especially .hyd-robromic acid.

40 Further ton-they are obtained by -=saponification of the compounds .acylatedat theoxygen and or lifltheinitrogen.

EXAMPLES cation of 1(p-hydro:cypheny1)-3'- clZylamino-b'utane 2.0 grs. of allyl bromide are added to a hot benzene" so1ution'of 5.0" grs; "0i 1- (p-h'ydroxypheiiyli '-3-ainino-butane;' "prepared according to the starting amine filtered with suction. The

motherliqlior is" .conce'ntrated, 'ifa necessary filoo- 'trat'ed again ifrom a: small quantity or non-con- (ll Prepar verted starting base and evaporated to dryness. The 1- (p-hydroxyphenyl) -3-allylamino-butane, which is obtained in almost quantitative yield, is converted with ethereal hydrobromic acid into the hydrobromide, which, after re-crystallization from acetone, melts at 116118 C. (uncorrected).

(2) Preparation of I-(p-hydroxyphenyD-3- cyclopentyl-amino-butane (3) Preparation of 1-(p-hydroxyphenyD-3- allylaminobutane l-(p-hydroxyphenyl)-3-brom-butane is prepared by heating a mixture of 5.0 grs. of l-(phydroxyphenyl)-3-oxy-butane, obtained accord.- ing to Mannich and Merz, Arch. Pharm., vol. 265, p. 22 (1927) and hydrogen bromide in glacial acetic acid for 3 hours to 100 C. After the glacial acetic acid has been distilled ofi in vacuo the obtained substance is purified by taking up in ether, shaking of the ethereal solution with a solution of bicarbonate, drying and evaporation of the ether. This starting material is heated to 120-130 C. with allyl amine in great excess in a bomb tube for five hours. The excess allyl amine is evaporated. The residue is taken up in diluted hydrochloric acid, and, in order to remove neutral bodies, extracted with ether. The acid solution is rendered alkaline by help of bicarbonate. The obtained base is taken up in ether. after having been distilled in high vacuo (boiling point 145-150 C. under 0.05 mm. pressure) is' converted into the hydrobromide, which melts after re-crystallization from acetone at 116-118 C. Adding on hydrobromide of same constitution prepared according to Example 1 there is no depression of the melting point to be observed.

(4) Preparation of 1-(p-hydroxyphenyD-3- methyZamino-butane 5.0 grs. of p-hydroxybenzyl-acetone are shaken with 0.95 gr. of methylamine, solved in absolute alcohol in the presence of platinum black in an atmosphere of hydrogen. An amount of hydrogen being taken up which corresponds to 1 mol. substance the substance is worked up according to Example 2. The hydrobromide of the 1- (p-hydrolxyphenyl) 3 methylamino butane melts after re-crystallization from water at 143 C.

(Si Preparation of I-(p-hydroxyphenyD-3- n-butylamz'no-butane 5.0 grs. of p-hydroxybenzylacetone and 2.3 grs. of n-butylamine solved in absolute alcohol are hydrogenated and worked up according to Exampl 4. The residue, after evaporation of the alcohol, is heated for some time in the waterbath under vacuo, in order to remove some remaining butylamine. The hydrobromide of the 1 (p hydroxyphenyl) -3-n-butylamin0 butane The ether is evaporated. The residue,,

melts after recrystallization from water at 170 C.

(6) Preparation of 1-(p-hydroxyphenyD-3- benzylamino-butane 5.0 grs. of p-hydroxybenzylacetone are hydrogenated with a solution of 3.3 grs. of benzylamine in absolute alcohol according to Example 4 and are worked up according to Example 5. The hydrobromide of the l-(p-hydroxyphenyl) 3-benzylamino-butane melts after re-crystallization from water at 158 C.

(7) Preparation of 1-(o-hydroaryphenyD-3- n-butylamino-butane 8.1 grs. of o-hydroxybenzal-acetone are treated with a solution of 3.7 grs. of n-butylamine. The red solution is shaken with platinum black in an atmosphere of hydrogen. 2 moles of hydrogen being taken up hydrogenation comes to a standstill. The solution, now practically colorless, is filtered from the catalyst, acidified with diluted hydrochloric acid and evaporated to dryness. The residue is crystallized from acetone after a small quantity of methanol is added. The hydrochloride of the l-(o-hydroxyphenyl) -3-n-butyltane melts at 143 C.

(8) Preparation of Z-(o-hydroztyphenyD-3- n-propylamtno-butane 8.1 grs. of o-hydroxybenzal-acetone was treated with 3.0 grs. of n-propylamine and worked up as described in Example 7. The hydrochloride of the 1 (o-hydroxyphenyl) -3-n-propylamino-butane melts at 143 C.

(9) Preparation of I-(m-hydrozcyphenyD-Ii-nbatyZamino-butane 8.1 grs. of m-hydroxybenzal-acetone are treated with butylamine and worked up as described in Example 7, a difierence only consisting in not using diluted hydrochloric acid but diluted hydrobromic acid for acidification. The hydrobromide of the '1- (m-hydroxyphenyl) -3-n-butylamino-butane melts at 117 C.

(10) Preparation of 1-(p-hydromyphenyD-3- ethyZamino-butane 8.1 grs. of p-hydroxybenzal-acetone are, according to Example 9, converted with 2.3 grs. of ethylamine and worked up. The hydrobromide of the l-(p-hydroxyphenyl) -3-ethylamino butane melts at 130 C.

(11) Preparation of 1-(p-hydromyphenyD-3-npropyl-amino-butane 8.1 grs. of p-hydroxybenzal-acetone are converted with 3.0 grs. of n-propylamine and worked up according to Example 9. The hydrobromide of the l-(p-hydroxyphenyl)-3-n-propylaminobutane melts at 138 C.

(12) Preparation of 1-(p-hydroxyphen1/D-3-namyZamzno-butane tained the nature of my said invention and. in what manner it is to be performed I declare that what I claim is:

1. 1 -(o-hydrou(ypheny1) -3-n butylamino-butane of the formula CHrCHr-CH-GH:

H-N--CHr-C HrCHr-CH:

3. A substituted butylamino-butane oi the formula HNOH -CHzOHz-OH: in which X is a hydroxyphenyl'radical. v

FRITZ KfiLZ. 

